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Clinical and Translational Medicine Oct 2023A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the...
BACKGROUND
A growing number of studies have shown that Yin Yang 1 (YY1) promotes the development of multiple tumours. The purpose of the current study was to determine the mechanism by which YY1 mediates neuroendocrine differentiation of prostate cancer (NEPC) cells undergoing cellular plasticity.
METHODS
Using the Cancer Genome Atlas and Gene Expression Omnibus (GEO) databases, we bioinformatically analyzed YY1 expression in prostate cancer (PCa). Aberrant YY1 expression was validated in different PCa tissues and cell lines via quantitative reverse transcription polymerase chain reaction, western blotting, and immunohistochemistry. In vivo and in vitro functional assays verified the oncogenicity of YY1 in PCa. Further functional assays showed that ectopic expression of YY1 promoted cellular plasticity in PCa cells via epithelial-mesenchymal transition induction and neuroendocrine differentiation.
RESULTS
Androgen deprivation therapy induced a decrease in YY1 protein ubiquitination, enhanced its stability, and thus enhanced the transcriptional activity of FZD8. Castration enhanced FZD8 binding to Wnt9A and mediated cellular plasticity by activating the non-canonical Wnt (FZD8/FYN/STAT3) pathway.
CONCLUSIONS
We identified YY1 as a novel dysregulated transcription factor that plays an important role in NEPC progression in this study. We believe that an in-depth investigation of the mechanism underlying YY1-mediated disease may lead to improved NEPC therapies.
Topics: Male; Humans; Prostatic Neoplasms; Wnt Signaling Pathway; Androgen Antagonists; Yin-Yang; Cell Differentiation; STAT3 Transcription Factor
PubMed: 37771187
DOI: 10.1002/ctm2.1422 -
NEJM Evidence Aug 2023BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life,...
BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life, and there remain no validated predictive models to guide its use. METHODS: We used digital pathology images from pretreatment prostate tissue and clinical data from 5727 patients enrolled in five phase 3 randomized trials, in which treatment was radiotherapy with or without ADT, as our data source to develop and validate an artificial intelligence (AI)–derived predictive patient-specific model that would determine which patients would develop the primary end point of distant metastasis. The model used baseline data to provide a binary output that a given patient will likely benefit from ADT or not. After the model was locked, validation was performed using data from NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 (n=1594), a trial that randomly assigned men to radiotherapy plus or minus 4 months of ADT. Fine–Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model–positive, i.e., benefited from ADT, and –negative subgroup treatment effects. RESULTS: Overall, in the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis. Of these enrolled patients, 543 (34%) were model positive, and ADT significantly reduced the risk of distant metastasis compared with radiotherapy alone. Of 1051 patients who were model negative, ADT did not provide benefit. CONCLUSIONS: Our AI-based predictive model was able to identify patients with a predominantly intermediate risk for prostate cancer likely to benefit from short-term ADT. (Supported by a grant [U10CA180822] from NRG Oncology Statistical and Data Management Center, a grant [UG1CA189867] from NCI Community Oncology Research Program, a grant [U10CA180868] from NRG Oncology Operations, and a grant [U24CA196067] from NRG Specimen Bank from the National Cancer Institute and by Artera, Inc. ClinicalTrials.gov numbers NCT00767286, NCT00002597, NCT00769548, NCT00005044, and NCT00033631.)
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Prostate-Specific Antigen; Artificial Intelligence; Hormones
PubMed: 38320143
DOI: 10.1056/EVIDoa2300023 -
JAMA Network Open Aug 2023Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting.
OBJECTIVE
To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients.
DESIGN, SETTING, AND PARTICIPANTS
This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023.
INTERVENTIONS
Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group).
MAIN OUTCOMES AND MEASURES
OS, with progression-free survival (PFS) as a secondary end point.
RESULTS
Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; P = .001) and had a higher median (IQR) baseline prostate-specific antigen response rate than White patients (54.7 [19.8-222.0] vs 26.7 [9.2-96.0] ng/mL; P < .001). At a median follow-up of 4.9 years, Black and White patients had similar median PFS (2.3 years; 95% CI, 1.8-1.4 years vs 2.9 years; 95% CI, 2.5-3.3 years; P = .71) and OS (5.5 years; 95% CI, 4.8-NR vs 6.3 years; 95% CI, 5.7-NR; P = .65). The multivariable analysis confirmed similar PFS and OS after adjusting for known prognostic factors. No interaction between race and treatment was observed.
CONCLUSIONS AND RELEVANCE
In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01809691.
Topics: Male; Humans; Aged; Prostatic Neoplasms; Androgen Antagonists; Prospective Studies; Androgens; Treatment Outcome; Androgen Receptor Antagonists; Castration
PubMed: 37526936
DOI: 10.1001/jamanetworkopen.2023.26546 -
Clinical Genitourinary Cancer Apr 2024Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus...
INTRODUCTION
Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC).
PATIENTS AND METHODS
We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI).
RESULTS
Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients.
CONCLUSIONS
Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.
Topics: Humans; Male; Androgen Antagonists; Antineoplastic Combined Chemotherapy Protocols; Austria; Docetaxel; Hormones; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Randomized Controlled Trials as Topic
PubMed: 38267304
DOI: 10.1016/j.clgc.2023.12.018 -
Asian Journal of Andrology Nov 2023The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other...
The final analysis of the phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial showed improvement in overall survival (OS) and other efficacy endpoints with apalutamide plus androgen deprivation therapy (ADT) versus ADT alone in patients with metastatic castration-sensitive prostate cancer (mCSPC). As ethnicity and regional differences may affect treatment outcomes in advanced prostate cancer, a post hoc final analysis was conducted to assess the efficacy and safety of apalutamide in the Asian subpopulation. Event-driven endpoints were OS, and time from randomization to initiation of castration resistance, prostate-specific antigen (PSA) progression, and second progression-free survival (PFS2) on first subsequent therapy or death. Efficacy endpoints were assessed using the Kaplan-Meier method and Cox proportional-hazards models without formal statistical testing and adjustment for multiplicity. Participating Asian patients received once-daily apalutamide 240 mg ( n = 111) or placebo ( n = 110) plus ADT. After a median follow-up of 42.5 months and despite crossover of 47 placebo recipients to open-label apalutamide, apalutamide reduced the risk of death by 32% (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.42-1.13), risk of castration resistance by 69% (HR: 0.31; 95% CI: 0.21-0.46), PSA progression by 79% (HR: 0.21; 95% CI: 0.13-0.35) and PFS2 by 24% (HR: 0.76; 95% CI: 0.44-1.29) relative to placebo. The outcomes were comparable between subgroups with low- and high-volume disease at baseline. No new safety issues were identified. Apalutamide provides valuable clinical benefits to Asian patients with mCSPC, with an efficacy and safety profile consistent with that in the overall patient population.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Prostate-Specific Antigen; Castration; Prostatic Neoplasms, Castration-Resistant
PubMed: 37322621
DOI: 10.4103/aja202320 -
Apalutamide for prostate cancer: Multicentre and multidisciplinary real-world study of 227 patients.Cancer Medicine Dec 2023To evaluate the efficacy and safety of apalutamide prostate cancer compared to the pivotal trials patients and to identify the first subsequent therapy in a real-world...
OBJECTIVE
To evaluate the efficacy and safety of apalutamide prostate cancer compared to the pivotal trials patients and to identify the first subsequent therapy in a real-world setting.
METHODS
The study is prospective and observational based on real-world evidence, performed by different medical disciplines and eight academics centres around Barcelona, Spain. It included all patients with metastatic hormone-sensitive prostate cancer (mHSPC) and high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treated with apalutamide from June 2018 to December 2022.
RESULTS
Of 227 patients treated with apalutamide, 10% had ECOG-PS 2, and 41% were diagnosed with new-generation imaging. In the mHSPC group (209 patients), 75 years was the median age, 53% had synchronous metastases, and 22% were M1a. In the nmCRPC (18 patients), 82 years was the median age, and 81% ≤6 months had PSA doubling time. Patients achieved PSA90 in 92% of mHSPC and 50% of nmCRPC and PSA ≤0.2 in 71% of mHSPC and 39% of nmCRPC. Treatment-related adverse events occurred in 40.1% of mHSPC and 44.4% of nmCRPC. After discontinuation of apalutamide due to disease progression, 54.5% in mHSPC and 75% in nmCRPC started chemotherapy, while after discontinuation because of adverse events, 73.3% in mHSPC and 100% in nmCRPC continued with other hormonal-therapies.
CONCLUSIONS
The efficacy and safety of apalutamide were similar to that described in the pivotal trials, despite including an older and more comorbid population. Usually, subsequent therapies after apalutamide differed depending on the reason for discontinuation: by disease progression started chemotherapy and by adverse events hormonal sequencing.
Topics: Male; Humans; Prostatic Neoplasms, Castration-Resistant; Prostate-Specific Antigen; Prospective Studies; Disease Progression; Androgen Antagonists
PubMed: 38063364
DOI: 10.1002/cam4.6769 -
Clinical Nutrition ESPEN Dec 2023Exercise is known to reduce adverse side effects of androgen-deprivation therapy (ADT) on quality of life, bone health and fatigue for prostate cancer (PCa) patients. We... (Meta-Analysis)
Meta-Analysis
Efficacy of multidisciplinary interventions in preventing metabolic syndrome and improving body composition in prostate cancer patients treated with androgen deprivation therapy: A systematic review and meta-analysis.
BACKGROUND
Exercise is known to reduce adverse side effects of androgen-deprivation therapy (ADT) on quality of life, bone health and fatigue for prostate cancer (PCa) patients. We conducted a systematic review with meta-analysis to evaluate the effect of multidisciplinary interventions on body composition and metabolic syndrome (MetS) in ADT-treated PCa patients.
METHODS
A systematic review and meta-analysis were conducted based on searches of EMBASE, MEDLINE, CENTRAL and Scopus databases from inception to March 2023. Participants included ADT-treated PCa patients who received multidisciplinary interventions including exercise, diet, nutrition, pharmacotherapy, bariatric surgery, or psychological/behavioural therapy. Primary outcomes were changes in body composition and MetS, with prostate-specific antigen (PSA) as a secondary outcome. After meta-analysis, results were reported in mean difference, 95% confidence interval and p-value, with forest plots. Additionally, we conducted subgroup analyses to compare the effect of different interventions.
RESULTS
Thirty-three articles met the eligibility criteria out of 1443 articles and 28 studies were included in meta-analysis. Of 33 studies, 17 included exercise-only interventions and 10 included exercise + diet/nutrition interventions, but no studies included diet/nutrition-only interventions. All studies employed multidisciplinary approaches in developing or delivering the interventions. Most studies (85%) had low-moderate risk of bias, thus providing good evidence to this review. Overall, interventions had a positive effect on body composition measures; lean mass (LM):0.82 kg (95% CI:0.47,1.17;p < 0.00001), body fat mass (BFM):-0.68 kg (95% CI:-1.12,-0.24;p = 0.002), fat-free mass:0.75 kg (95% CI:0.14,1.37;p = 0.02) and body fat percentage (BFP):-0.99% (95% CI:-1.29,-0.68;p < 0.00001), as well as on MetS; waist circumference:-1.95 cm (95% CI:-3.10,-0.79;p = 0.0009), systolic blood pressure:-3.43 mmHg (95% CI:-6.36,-0.50;p = 0.02) and diastolic blood pressure:-2.48 mmHg (95% CI:-4.19,-0.76;p = 0.005). Subgroup-analyses showed that a combined approach including exercise + diet/nutrition was most effective in improving BFP, WC, SBP and DBP whereas exercise was more effective in improving LM and BFM.
CONCLUSIONS
In ADT-treated PCa patients, multidisciplinary interventions, especially those combining exercise and diet/nutrition, can improve body composition and metabolic health.
Topics: Male; Humans; Prostatic Neoplasms; Androgen Antagonists; Androgens; Metabolic Syndrome; Quality of Life; Body Composition
PubMed: 38057016
DOI: 10.1016/j.clnesp.2023.09.001 -
Frontiers in Oncology 2023Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality... (Review)
Review
Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.
PubMed: 37664036
DOI: 10.3389/fonc.2023.1193736 -
Hellenic Journal of Nuclear Medicine 2023We aimed to evaluate the efficacy oflutetium-177-prostate-specific membrane antigen-617 (Lu-PSMA-617) with the luteinizing hormone releasing hormone (LHRH) analogues in...
Lutetium-177-PSMA-617 radioligand therapy in patients with high volume metastatic prostate cancer prior to chemotherapy and new generation androgen deprivation therapy: Clinical Experience.
OBJECTIVE
We aimed to evaluate the efficacy oflutetium-177-prostate-specific membrane antigen-617 (Lu-PSMA-617) with the luteinizing hormone releasing hormone (LHRH) analogues in the first or in the second-line setting formetastatic castration sensitive patients and metastatic castration resistance after progression with LHRH analogues.
SUBJECTS AND METHODS
Sixteen consecutive patients with high volume metastatic prostate cancer undergone Lu-PSMA-617 therapy who were refused chemotherapy and were unable to use new generation anti-androgen drugs because of unavailibility of reimbursement, were included in this retrospective study. Prostate specific antigen (PSA) response (>50% decrease), disease control rate (DCR: complete or partial response), progression-free survival (PFS) and overall survival (OS) were calculated to evaluate according to the clinicopathological features of the patients. Treatment response evaluated by Ga-PSMA-11 positron emission tomography/computed tomography (PET/CT).
RESULTS
Mean age was 74,6 (SD±8,36). Among them, 7 (43,8%) patients has castration resistant disease, while the remaining has castration sensitive disease. Lutetium-177-PSMA-617 was administered to 10 (62,5%) patients as one of the first-line treatment and 6 patients received the treatment after progression on LHRH as a second-line treatment. Considering all patients, PSA response rate and DCR were 50% and 62% respectively. The median PFS and OS (with 95% CI) were 11,2 months (11-15) and 29 months (25,6-32,4), respectively in patients treated with Lu-PSMA-617 and LHRH analogues. Clinicopathological features and basal PSA level did not have effect on PSA response rates, DCR, OS and PFS. On the other hand, increment in PFS and OS (with 95% CI) was observed in castration resistant disease and in the second-line therapy; for castration resistant disease 16,5 months (12.3-19.7); 30 months (25.3-32.7), for the second-line therapy 14.5 months (12-20.5); 29 months (NR), respectively but statistically not significant. Serious toxicity was observed in a limited number of patients (18,7%), treatment-related death was not observed.
CONCLUSION
Favorable results can be achived with second-line Lu-PSMA-617 treatment in terms of OS and PFS, especially in castration-resistant disease, when chemotherapy and new generation ADT's cannot be used.
Topics: Male; Humans; Prostate-Specific Antigen; Androgen Antagonists; Androgens; Positron Emission Tomography Computed Tomography; Treatment Outcome; Retrospective Studies; Prostatic Neoplasms, Castration-Resistant; Gonadotropin-Releasing Hormone
PubMed: 38085834
DOI: 10.1967/s002449912603 -
Lakartidningen Apr 2024There is a long history of curative treatment of prostate cancer. However, as prostate cancer often grows very slowly, and symptoms do not have time to develop during a... (Review)
Review
There is a long history of curative treatment of prostate cancer. However, as prostate cancer often grows very slowly, and symptoms do not have time to develop during a person's lifetime, a more tentative approach has become more and more common in many cases. This may be through either watchful waiting or active surveillance. In the first case palliative hormonal treatment is given in the case of progression, in the latter curative treatment would be the choice. When treatment is deemed necessary for localized disease, surgery and radiotherapy are considered equivalent in terms of efficacy and overall risk of side effects. For locally advanced disease, radiotherapy is the recommended first-hand choice outside the SPCG 15 study. Focal treatment, which may lead to less side effects than surgery or radiotherapy, is not recommended outside trial settings due to lack of long-term follow-up data.
Topics: Humans; Male; Prostatic Neoplasms; Watchful Waiting; Prostatectomy; Androgen Antagonists; Palliative Care
PubMed: 38650398
DOI: No ID Found